US11814355B2 - Method for synthesizing pitavastatin t-butyl ester - Google Patents

Method for synthesizing pitavastatin t-butyl ester Download PDF

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US11814355B2
US11814355B2 US17/173,171 US202117173171A US11814355B2 US 11814355 B2 US11814355 B2 US 11814355B2 US 202117173171 A US202117173171 A US 202117173171A US 11814355 B2 US11814355 B2 US 11814355B2
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US20220041556A1 (en
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Huan Huang
Kai Li
Qingyun Huang
Fuming ZHAN
Qingguo Huang
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ANHUI QINGYUN PHARMACEUTICAL AND CHEMICAL Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D215/14—Radicals substituted by oxygen atoms
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J23/00—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00
    • B01J23/16—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of arsenic, antimony, bismuth, vanadium, niobium, tantalum, polonium, chromium, molybdenum, tungsten, manganese, technetium or rhenium
    • B01J23/24—Chromium, molybdenum or tungsten
    • B01J23/28—Molybdenum
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J23/00—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00
    • B01J23/16—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of arsenic, antimony, bismuth, vanadium, niobium, tantalum, polonium, chromium, molybdenum, tungsten, manganese, technetium or rhenium
    • B01J23/24—Chromium, molybdenum or tungsten
    • B01J23/30—Tungsten
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J27/00—Catalysts comprising the elements or compounds of halogens, sulfur, selenium, tellurium, phosphorus or nitrogen; Catalysts comprising carbon compounds
    • B01J27/20—Carbon compounds
    • B01J27/232—Carbonates
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J27/00—Catalysts comprising the elements or compounds of halogens, sulfur, selenium, tellurium, phosphorus or nitrogen; Catalysts comprising carbon compounds
    • B01J27/24—Nitrogen compounds
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B01J31/12—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides containing organo-metallic compounds or metal hydrides
    • B01J31/121—Metal hydrides
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B01J31/12—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides containing organo-metallic compounds or metal hydrides
    • B01J31/122—Metal aryl or alkyl compounds
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B01J31/12—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides containing organo-metallic compounds or metal hydrides
    • B01J31/128—Mixtures of organometallic compounds
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/10—Complexes comprising metals of Group I (IA or IB) as the central metal
    • B01J2531/11—Lithium
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/10—Complexes comprising metals of Group I (IA or IB) as the central metal
    • B01J2531/12—Sodium
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B01J31/0201—Oxygen-containing compounds
    • B01J31/0211—Oxygen-containing compounds with a metal-oxygen link
    • B01J31/0212—Alkoxylates
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B01J31/0272—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides containing elements other than those covered by B01J31/0201 - B01J31/0255
    • B01J31/0274—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides containing elements other than those covered by B01J31/0201 - B01J31/0255 containing silicon

Definitions

  • the present invention relates to the field of chemical synthesis, and in particular, to a method for synthesizing pitavastatin t-butyl ester.
  • Pitavastatin calcium is the first fully synthesized HMG-CoA reductase inhibitor jointly developed by the Nissan Chemical and Kowa Company, Ltd.; it is a statin drug. It mainly reduces the ability of the liver to produce cholesterol by inhibiting the liver enzyme of HMG-CoA reductase, thereby improving the blood cholesterol level after elevated. 6-[[(1E)-2-Cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-vinyl]-2,2-dimethyl-1,3-dioxane-4-acetate tert-butyl ester, which may simply call pitavastatin tert-butyl ester, which is the key intermediate of pitavastatin calcium. In existing pitavastatin calcium synthesis routes, most require the synthesis of this intermediate.
  • the synthetic route 1 is as follows:
  • the synthetic route 2 is the preparation method of pitavoctambutyl tert-butyl ester reported in China Patent Number CN102174039A, which utilizes (4R,6S)-6-hydroxymethyl-2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester as the starting material to react with 1,1′-(1.4-phenylene)-bis-(1H-tetrazole-5-thiol) and di isopropyl azodicarboxylate and subjected to Mitsunobu reaction, then the sulfone compound is obtained through oxidation reaction, and finally the pitavastatin tert-butyl ester is obtained under alkaline conditions with 2-cyclopropyl-4-(4-fluorophenyl) quinoline-3-formaldehyde.
  • the method is relatively harsh in reaction conditions, which requires an ultra-low temperature reaction, and in the oxidation process, because the steric hindrance is high, the selectivity of the conversion is influenced due to a small amount of remaining sulphoxide, which affects the yield and purity of the next reaction. There is a need for multiple column chromatography, and the yield is relatively low.
  • the synthetic route 2 is as follows:
  • the problem existing in the synthesis method of pitavoctambutyl tert-butyl ester is mainly poor in stereoselectivity, relatively harsh in reaction conditions, incomplete in intermediate oxidation, required for multiple column chromatography, low in yield, and not suitable for industrial production.
  • the present invention provides a novel synthetic method of pitavastatin tert-butyl ester.
  • the method is mild in reaction condition, good in stereoselectivity, high in yield, high in purity, and easy for industrial production.
  • the present invention addresses the above-mentioned problems by the following solutions.
  • the present invention provides a method for synthesizing pitavastatin tert-butyl ester, including the following steps:
  • obtaining a substance B through reacting (4R-CIS)-6-chloromethyl-2,2-dimethyl-1,3-dioxolane-4-acetic acid tert-butyl ester with a substance A under the action of a first base catalyst; oxidizing with an oxidizing agent to obtain a substance C; then reacting with 2-cyclopropyl-4-(4-fluorophenyl)-quinoline-3-formaldehyde under the action of a second base catalyst to obtain a substance D; finally, carrying out an acid deprotection to obtain pitavastatin t-butyl ester.
  • the synthetic route is as follows:
  • R is selected from the group consisting of hydrogen, alkyl, cycloalkyl, phenyl, and substituted phenyl, and is, preferably, hydrogen or alkyl.
  • the first base catalyst is selected from the group consisting of sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, and combinations thereof.
  • the first base catalyst is sodium carbonate.
  • the oxidizing agent is a hydrogen peroxide system or a m-chloroperoxybenzoic acid, and preferably the oxidizing agent is a hydrogen peroxide system.
  • the hydrogen peroxide system is a mixture of hydrogen peroxide and a catalyst, wherein the catalyst is selected from the group consisting of ammonium molybdate tetrahydrate, sodium tungstate, and combination thereof, wherein preferably, the catalyst is ammonium molybdate tetrahydrate.
  • the second base catalyst is selected from the group consisting of sodium methoxide, sodium ethoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydride, bis-(trimethylsilyl)-amino lithium, bis-(trimethylsilyl)-amino sodium, bis-(trimethylsilyl)-amino sodium potassium, and combinations thereof.
  • the second base catalyst is sodium hydride.
  • the molar ratio of the substance A to the first base catalyst is 1:0.5-5.
  • the molar ratio of the substance A to the first base catalyst is 1:1-2.
  • the molar ratio of (4R-CIS)-6-chloromethyl-2,2-dimethyl-1,3-dioxolane-4-acetic acid tert-butyl ester to substance A is 1:1.1-1.5, preferably 1:1.1-1.3.
  • the reaction solvent for the synthesized substance B is selected from the group consisting of N, N-dimethylformamide, N, N-dimethylacetamide, toluene, xylene, N-methylpyrrolidone, 1,4-dioxane, and combinations thereof.
  • the reaction solvent of the synthesized substance B is 1,4-dioxane.
  • the weight ratio of the reaction solvent of the synthesized substance B to (4R-Cis)-6-chloromethyl-2,2-dimethyl-1,3-dioxolane-4-acetic acid tert-butyl ester is 1-20:1.
  • the weight ratio of the reaction solvent of the synthetic substance B to (4R-Cis)-6-chloromethyl-2,2-dimethyl-1,3-dioxolane-4-acetic acid tert-butyl ester is 5-10:1.
  • the reaction temperature of the synthesized substance B is 10-100° C. Preferably, the reaction temperature of the synthesized substance B is 30-80° C.
  • the molar ratio of the substance B to the catalyst is 1:0.01-0.5, wherein preferably, the molar ratio of the substance B to the catalyst is 1:0.03-0.1, wherein the molar ratio of the substance B to the hydrogen peroxide is 1:1-20.
  • the molar ratio of the substance B to the hydrogen peroxide is 1:4-10.
  • the molar ratio of the substance B to the m-chloroperoxybenzoic acid is 1:2-10, and preferably, the molar ratio of the substance B to the m-chloroperoxybenzoic acid is 1:2-4.
  • the temperature of the oxidation reaction is 0-100° C., and preferably, the temperature of the oxidation reaction is 20-40° C.
  • the oxidation reaction solvent is an alcohol solvent, such as methanol, ethanol, isopropanol, combinations thereof, and etc.
  • the oxidation reaction solvent is isopropanol.
  • the weight ratio of the reaction solvent of the synthesized substance C to the substance B is 1-20:1. Preferably, the weight ratio of the reaction solvent of the synthesized substance C to the substance B is 5-10:1.
  • the molar ratio of the substance C to the second base catalyst is 1:0.5-10.
  • the molar ratio of the substance C to the second base catalyst is 1:1-6.
  • the molar ratio of the substance C to the 2-cyclopropyl-4-(4-fluorophenyl)-quinoline-3-formaldehyde is 1:1:01-1.3, and preferably is 1:1.01-1.1.
  • the temperature of the synthesized substance D is ⁇ 40° C.-20° C.
  • the temperature of the synthesized substance D is ⁇ 10° C.-10° C.
  • the reaction solvent of the synthesized substance D is selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, N-methylpyrrolidone, N, N-dimethylformamide, N, N-dimethylacetamide, toluene, dichloromethane, 1.2-dichloroethane, and combinations thereof.
  • the solvent of the synthesized substance D is tetrahydrofuran.
  • the substance C and 2-cyclopropyl-4-(4-fluorophenyl)-quinoline-3-formaldehyde are added to the solvent and stirred and dissolved at room temperature, and then the mixture is cooled to about 0° C., wherein the second base catalyst is slowly added in batches, and the temperature is controlled for continuing the reaction.
  • composition D further comprises the steps of concentrating, recrystallizing, and etc.
  • the solvent in the last step reaction is selected from the group consisting of acetonitrile, toluene, xylene, and combinations thereof.
  • the solvent for the hydrolysis is acetonitrile.
  • the acid in the last step reaction is an acid capable of removing ether protecting groups, such as hydrochloric acid, sulfuric acid, and etc., and the preferable acid is hydrochloric acid.
  • the concentration of the aqueous hydrochloric acid solution is 0.01-1 mol/L in the deprotection process.
  • the concentration of the aqueous hydrochloric acid solution is 0.02-0.2 mol/L.
  • the alkyl group of the present invention refers to a linear or branched alkyl group containing 1 to 6 carbon atoms, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, iso-pentyl, n-hexyl, and etc.
  • cycloalkyl refers to a saturated monocyclic cyclic hydrocarbon substituent containing from 3 to 6 carbon atoms, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and etc.
  • the substituted phenyl described in the present invention refers to one, two or more substitutions at any location(s) on the benzene ring.
  • the substituent is selected from the group consisting of hydrogen, halogen, nitro, cyano, C, 1-C4 alkyl.
  • the C, 1-C4 alkyl refers to a linear chain or branched chain alkyl group containing 1 to 4 carbon atoms, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and etc.
  • reagents without specified source in the present invention are regular or conventional reagents available on the market.
  • the present invention has the following beneficial effects:
  • FIG. 1 is a nuclear magnetic hydrogen spectrum diagram of the substance B according to a preferred embodiment 1 of the present invention.
  • FIG. 2 is a nuclear magnetic hydrogen spectrum diagram of the substance C according to the above preferred embodiment 1 of the present invention.
  • FIG. 3 is a nuclear magnetic hydrogen spectrum diagram of the substance D according to the above preferred embodiment 1 of the present invention.
  • FIG. 4 is a nuclear magnetic hydrogen spectrum diagram of the pitavastatin tert-butyl ester.
  • the substituent of the substance A is cyclopropyl, whereas the rest of the conditions and feeding ratios are consistent to Embodiment 1.
  • the substituent of the substance A is hydrogen base, whereas the rest of the conditions and feeding ratios are consistent to Embodiment 1.
  • the first base catalyst is sodium bicarbonate, and the molar ratio of the substance A to the sodium bicarbonate is 1:0.5.
  • the second base catalyst is sodium methoxide, and the molar ratio of the substance C to the sodium methoxide is 1:0.5.
  • the ammonium molybdate tetrahydrate is replaced with sodium tungstate in the oxidation reaction; the rest is consistent with Embodiment 1.
  • the first base catalyst is potassium bicarbonate, and the molar ratio of the substance A to the potassium bicarbonate is 1:5.
  • the second base catalyst is bis-(trimethylsilyl)-amino lithium, and the molar ratio of the substance C to the bis-(trimethylsilyl)-amino lithium is 1:10. The rest is consistent with Embodiment 1.
  • the temperature of the synthesized substance B is 10° C. and the time is 8 hours.
  • the oxidation temperature is 0° C., and the oxidation time is 48 hours. The rest is consistent with Embodiment 1.
  • the temperature of the synthesized substance B is 100° C. and the time is 2 hours.
  • the oxidation temperature is 100° C., and the oxidation time is 12 hours. The rest is consistent with Embodiment 1.
  • the reaction conditions of the present invention are mild, the stereoselectivity is good, and there is no cis-isomer in the obtained pitavastatin tert-butyl ester, which purity and yield are high.

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CN112028881B (zh) * 2020-09-02 2023-08-15 能特科技有限公司 一种瑞舒伐他汀钙的高级中间体r-1的合成方法
CN113387944B (zh) * 2021-07-09 2021-12-28 浙江宏元药业股份有限公司 一种瑞舒伐他汀钙中间体的合成方法
CN113754650B (zh) * 2021-08-06 2023-10-20 湖北宇阳药业有限公司 一种瑞舒伐他汀钙中间体的高选择性合成方法
CN115754025B (zh) * 2021-09-02 2024-07-02 上虞京新药业有限公司 一种匹伐他汀钙中基因毒性杂质gti的检测方法

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WO2007132482A2 (en) * 2006-05-17 2007-11-22 Manne Satyanarayana Reddy Novel process for the preparation of pitavastatin and its pharmaceutically acceptable salts
CN102174039A (zh) * 2011-03-10 2011-09-07 上海交通大学 高光学纯匹伐他汀钙关键中间体的制备方法
US8829186B2 (en) * 2010-01-20 2014-09-09 Cadila Healthcare Limited Method for preparation of pitavastatin and pharmaceutical acceptable salts thereof

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CN109574999B (zh) * 2017-09-28 2022-03-08 安徽省庆云医药股份有限公司 一种匹伐他汀钙中间体的制备方法
CN110483412B (zh) * 2019-09-17 2020-06-26 安徽省庆云医药股份有限公司 一种瑞舒伐他汀叔丁酯的合成方法

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007132482A2 (en) * 2006-05-17 2007-11-22 Manne Satyanarayana Reddy Novel process for the preparation of pitavastatin and its pharmaceutically acceptable salts
US8829186B2 (en) * 2010-01-20 2014-09-09 Cadila Healthcare Limited Method for preparation of pitavastatin and pharmaceutical acceptable salts thereof
CN102174039A (zh) * 2011-03-10 2011-09-07 上海交通大学 高光学纯匹伐他汀钙关键中间体的制备方法

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